We are continuing to study the role of humoral and cellular immunity in controlling and preventing HIV infection. Using primary patient isolates, we have investigated humoral immune responses of infected patients to their own viruses. We have observed a complex pattern of autologous virus sensitivity and epitope specificity in infected patients. Asymptomatic patients harbor MT virus types that are resistant to anti-V3 specific antibodies while being partially sensitive to high concentrations of antiserum through non-V3 epitopes. Several asymptomatic patients also had T cell tropic isolates that were neutralized with autologous and heterologous antibodies through both V3 or non-V3 epitopes. In contrast, AIDS patients lost neutralizing antibodies to both autologous and heterologous viruses, and HIV isolates from these patients were antibody resistant. Antibody responses to gp120 and gp160 vaccines have been evaluated for reactivity to cell surface oligomeric forms of envelope. Antibodies generated to clade B envelopes in immunized animals and humans were found to cross react with native envelopes from both MT and TCT isolates from different clades. Binding activity did not correlate with neutralizing activity. We have also studied the cellular immune response to HIV and are addressing the relationship between spontaneous apoptosis in different T cell subsets in HIV infected patients and the ability to generate cytolytic effector activity against MHC presented viral proteins. A major obstacle to AIDS vaccine and therapeutic development is the incomplete understanding of what constitutes protective immunity to HIV-1. Novel assays with monoclonal antibodies and type specific antisera should provide methods to immunotype patient isolates and to evaluate humoral responses to HIV vaccine candidates in clinical trials. Studies are planned on understanding the impact of humoral immunity on heterosexual virus transmission. Assays developed during the course of our studies are being applied to characterize the types of viruses heterosexually transmitted and to evaluate antiviral compounds for use in vaginal products.